Receptor-mediated effects on oligodendrocyte phenotype and disease. The objectives of this ongoing continuation are to define the paired interactions of the erbB family and TNF family of receptors that influence the development and differentiation of oligodendrocytes (OL). TNF family members are thought relevant to OL death in multiple sclerosis (MS), and we hypothesize that their activity influences the function of erbB receptor members on OL cells. We will use a variety of approaches to determine the biochemical basis of the paired relationship of these receptor families and how they guide maturation driven by erbB ligands in vitro and in vivo. In the course of the efforts we hope to identify signaling pathways that are most relevant to mitotic growth of OL precursors and those that lead to maturation to functional OL cells. Attempts will be made to correlate differentiation of OL with cyclin dependent kinase inhibitor accumulation. Efforts to modify TNF activity in vivo by macromolecular therapy alone have been unsuccessful. We have developed a novel class of secondary structure exocyclic peptides and cystine knot mimetics that may limit TNF receptor signaling in a way beneficial to MS therapy, especially if coupled to erbB growth factor receptor activation. This new class of secondary structural exocyclics and cystine knot forms designed from the TNF receptor structure will be used in vivo in attempts to modify the immunologically driven oligodendrocyte death seen in the experimental allergic encephalomyelitis (EAE) model. Extensive collaborations with Dr. Rostami, Dr. Pleasure, and Dr. Chen will be important during the course of these studies. Basic principles resolved by these studies may have relevance to multiple sclerosis therapy.